This is a request for renewal of an RSA. The purpose of my research is to enhance the understanding of cognitive processes in the human brain through behavioral, anatomical, and physiological studies in nonhuman primates. The main focus is on the principal sulcus (PS) (Walkers'area 46) of the macaque dorsolateral prefrontal cortex; this region of the primate cortex is essential for the process of working memory, which underlies a wide range of cognitive processes in humans including comprehension, reasoning, and planning for the future. The specific plan for the next five years is to continue neurobiological studies of the spatial memory functions of the PS at the areal, network, column and single cell levels. A series of anatomical studies will combine pathway tracing and electrophysiology and, in some instances immunocytochemistry, to examine selected visual, motor and intrinsic connections of prefrontal columns upon which memory functions are mapped (Specific Aim #1). In complementary studies, a battery of functional approaches, e.g., intracortical injections of bicucculine for temporary disruption of function (Specific Aim #2), single- and double-label 2-deoxyglucose (Specific Aims #3 and #4) and finally single cell recording studies (Specific Aim #5) will be conducted in animals trained to perform memory-guided and sensory-guided oculomotor delayed response tasks. These studies are designed to provide a comprehensive analysis of the topography and dynamics of working memory in prefrontal cortex and a test of the hypothesis that areas anatomically interconnected with the PS are dedicated to spatial cognition, each making a distinctive contribution. In addition, the RSA supported studies on nonhuman primates have implications for understanding the causes and symptoms of schizophrenia, the mental disease in which frontal lobe dysfunction is most prominent. Through my role as P.I.. of an NIMH funded Center for Neuroscience Research in Schizophrenia, I will be engaged directly in immunocytochemical, cytological, and receptor autoradiographic studies of schizophrenic cortex and, in general, the Center will develop primate models by manipulating cortical development in utero and also by lesion and drug induction of symptoms such as deficits in predictive eye tracking, memory and perseverative behavior. The proposed studies should advance our understanding of the circuit and cellular basis of cognitive functions, their development in ontogeny and their dissolution in mental disease.